Dry powder compositions for intranasal delivery

Abstract

Dry powder pharmaceutical compositions for intranasal administration include an opioid receptor antagonist, e.g. naloxone, as active ingredient, and dosage unit forms thereof. Methods of treating opioid overdose include administering the dry powder compositions.

The invention claimed is: 
     
       1. A pharmaceutical composition in a form of dry powder for intranasal administration, comprising at least one opioid receptor antagonist as active ingredient, said composition comprising (1) at least one opioid receptor antagonist solid particles and (2) pharmaceutically acceptable disaggregating agent solid particles, wherein at least 90% of said one opioid receptor antagonist solid particles are of a mean particle size of about 10 to about 30 microns, and less than about 10% of said at least one opioid receptor antagonist solid particles are of a mean particle size equal to or below about 10 microns and said pharmaceutically acceptable disaggregating agent solid particles are of a mean particle size greater than that of said at least one opioid receptor antagonist solid particles. 
     
     
       2. The pharmaceutical composition according to  claim 1 , wherein less than about 5% of said at least one opioid receptor antagonist solid particles are of a mean particle size of or below 5 microns. 
     
     
       3. The pharmaceutical composition of  claim 1 , wherein said pharmaceutically acceptable disaggregating agent solid particles are of a mean size of about 50 to about 200 microns. 
     
     
       4. The pharmaceutical composition of  claim 1 , wherein said pharmaceutically acceptable disaggregating agent solid particles are of a mean size of about 50 to about 150 microns. 
     
     
       5. The pharmaceutical composition of  claim 1 , wherein said at least one opioid receptor antagonist solid particles are of a substantially spherical form and said pharmaceutically acceptable disaggregating agent solid particles are of an irregular shape. 
     
     
       6. The pharmaceutical composition of  claim 1 , comprising said disaggregating agent as the only excipient for preventing aggregation of the dry powder particles of the active ingredient and preserving their original size and shape in said composition. 
     
     
       7. The pharmaceutical composition of  claim 1 , wherein said at least one opioid receptor antagonist is any one of naloxone, naltrexone, almivopan, methylnaltrexone, naloxegon or naldemidine and pharmaceutically acceptable salts thereof and solvates or hydrates thereof, wherein said salt is any of chloride, bromide, oxalate, or tosylate. 
     
     
       8. The pharmaceutical composition of  claim 1 , wherein said disaggregating agent is any one of lactose monohydrate, lactose, a lactose functional analogue, dextrose, sorbitol, mannitol, maltitol and xylitol, a cellulose or cellulose derivative, or starch or starch derivative, or any mixture of at least two thereof. 
     
     
       9. The pharmaceutical composition of  claim 1 , wherein the weight ratio between said at least one opioid receptor antagonist solid particles and said pharmaceutically acceptable disaggregating agent solid particle is between about 1:9 to about 9:1. 
     
     
       10. A disposable dose unit for single intranasal administration to a subject of a pharmaceutical composition according to  claim 1 , wherein said dose unit is loaded with a predetermined dose of the composition and provides the subject with a therapeutically effective metered dose of said opioid receptor antagonist. 
     
     
       11. A method of treating opioid overdose/intoxication and/or a symptom thereof in a patient in need thereof, said method comprising intranasally administering to said patient a therapeutically effective amount of a composition as defined in  claim 1 . 
     
     
       12. The method of  claim 11 , wherein said symptom associated with opioid overdose/intoxication is any one of respiratory depression, central nervous system depression, cardiovascular depression, altered level consciousness, miotic pupils, hypoxemia, acute lung injury, aspiration pneumonia, sedation, hypotension, unresponsiveness to stimulus, unconsciousness, stopped breathing; erratic or stopped pulse, choking or gurgling sounds, blue or purple fingernails or lips, slack or limp muscle tone, contracted pupils, and vomiting. 
     
     
       13. The method of  claim 11 , further comprising administration of an opioid, wherein said opioid is administered simultaneously with said opioid receptor antagonist or separately. 
     
     
       14. The method of  claim 11 , wherein said intranasal administration results in over 50% of said at least one opioid receptor antagonist solid particles reaching turbinates region in the intranasal cavity, and less than 1% of said at least one opioid receptor antagonist solid particles reaching the lungs of said patient. 
     
     
       15. A naloxone pharmaceutical composition in the form of dry powder for intranasal administration, comprising as active agent naloxone or a pharmaceutically acceptable salt thereof, said composition comprising (1) naloxone or pharmaceutically acceptable salt thereof solid particles, and (2) lactose monohydrate solid particles as disaggregation agent, wherein at least about 90% of said naloxone or pharmaceutically acceptable salt thereof solid particles are of a mean particle size of about 10-30 microns and less than about 10% of said naloxone or pharmaceutically acceptable salt thereof solid particles are of a mean particle size equal to or below about 10 microns and said lactose monohydrate solid particles are of a mean particle size greater than that of said naloxone or pharmaceutically acceptable salt thereof solid particles, providing a metered therapeutically effective nominal dose of said naloxone or pharmaceutically acceptable salt thereof. 
     
     
       16. The naloxone pharmaceutical composition of  claim 15 , comprising 20% w/w, 15% w/w, 10% w/w, 8% w/w or 5% w/w naloxone or said pharmaceutically acceptable salt thereof or solvate or hydrate thereof. 
     
     
       17. The naloxone pharmaceutical composition of  claim 15 , wherein said therapeutically effective nominal dose of said naloxone is 4 mg. 
     
     
       18. A disposable dose unit for single intranasal administration to a subject of a naloxone pharmaceutical composition according to  claim 15 , wherein said dose unit is loaded with a predetermined dose of the composition and provides the subject with a therapeutically effective metered dose of naloxone or said pharmaceutically acceptable salt thereof. 
     
     
       19. The disposable dose unit of  claim 18 , wherein said therapeutically effective metered dose of naloxone or said pharmaceutically acceptable salt thereof is 4 mg per single administration. 
     
     
       20. A kit for intranasal administration of naloxone comprising:
 a. at least one dose unit for single intranasal administration comprising a naloxone pharmaceutical composition as defined in  claim 15 ; and 
 b. instructions for use. 
 
     
     
       21. A method of treating opioid overdose/intoxication and/or a symptom thereof in a patient in need thereof, said method comprising intranasally administering to said patient a therapeutically effective dose of a composition as defined in  claim 15 . 
     
     
       22. The method of  claim 21 , wherein administration of said therapeutically effective dose is repeated at 2 to 3 minute intervals, up to a cumulative dose of from about 8 mg to about 10 mg and up to about 15 mg of naloxone. 
     
     
       23. The method of  claim 21 , further comprising administration of an opioid, wherein said opioid is administered simultaneously with said naloxone or separately.